1. Technical Field of the Invention
The present invention relates to the formulation of bioactive ingredients for the purpose of pharmaceutical applications, in particular for topical application/administration.
The present invention relates, in particular, to a novel process for solubilizing metronidazole in a pharmaceutical composition, by combining, in an aqueous phase, at least metronidazole, niacinamide, propylene glycol and polyethylene glycol. Such combinations make it possible to solubilize the metronidazole therein.
This invention also relates to the solutions/compositions formulated via the subject solubilization process, to the method for preparing same, to the resulting compositions containing the metronidazole thus solubilized, and to the administration thereof in human or veterinary medicine.
2. Description of Background and/or Related and/or Prior Art
Metronidazole, or 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, has long been known as a bioactive compound in the treatment of various conditions and afflictions, and in particular in the treatment of diseases due to various protozoa. When applied topically, metronidazole is also used in the treatment of various dermatological conditions, including rosacea (acne rosacae), bacterial ulcers and periorale dermatitis, as described in U.S. Pat. No. 4,837,378. Metronidazole also exhibits an anti-inflammatory activity when it is applied topically in the treatment of dermatological disorders, as described in U.S. Pat. No. 5,849,776. Metronidazole can also be used in the treatment of bacterial vaginosis, as an intravaginal therapeutic agent, as described in U.S. Pat. No. 5,536,743.
The compositions containing metronidazole for the treatment of dermatological disorders/afflictions are available in the form of a cream, a gel or a lotion. Noritate™ (Dermik Laboratories, Inc.) contains 1% of metronidazole dispersed in a white cream. Galderma Laboratories, Inc proposes MetroGel®, containing 0.75% by mass, relative to the total mass of the composition (m/m), of metronidazole solubilized in a transparent gel, MetroCream® containing 0.75% (m/m) of metronidazole solubilized in an emollient cream, and MetroLotion® containing 0.75% (m/m) of metronidazole solubilized in a lotion.
In the case of topical applications, products containing the active ingredient in solubilized form often exhibit better bioavailability than products in which the active ingredient is dispersed.
Given the low intrinsic solubility of metronidazole in an aqueous phase, which is on the order of 0.9% (m/m), the gelled aqueous compositions currently available on the market are limited to a concentration of 0.75% (m/m) of metronidazole, solubilized in the formulation. The metronidazole formulations in the form of creams have the advantage, over the gelled formulations currently available, of containing 1% (m/m) of metronidazole.
In general, the solubility of the active ingredients in an aqueous phase may be increased by including various non-ionic or ionic surfactants, lipid derivatives such as lecithins which allow the formation of lipid micelles, or cyclodextrins as often described in the literature.
Cyclodextrins make it possible to increase the water-solubility of various compounds. Cyclodextrins are in the form of a cage. The hydrophilic external part of this cage confers on them a certain solubility in aqueous media. Their inner part, which is more hydrophobic, allows the solubilization of amphiphilic or lipophilic molecules through the formation of inclusion complexes. The water-solubility of many molecules can therefore be substantially increased by employing these cyclodextrins. However, cyclodextrins have drawbacks in terms of cost, of limited solubility, of incompatibility with certain carriers or excipients, or of potential local or systemic toxicity. Furthermore, the formation of the inclusion complexes, complexation step, can be quite long, commonly several hours, and can affect the costs and processes for manufacturing the formulations.
Solubility-increasing agents other than cyclodextrins have been described. Yie W. Chien, Journal of Parenteral Science and Technology, 38 (1): 32-36 (January 1984), shows that the solubility of metronidazole in an aqueous solution can be increased by means of water-soluble vitamins such as niacinamide, pyridoxine hydrochloride and ascorbic acid. Chien subsequently describes that the water-solubility of metronidazole increases in a linear manner in relation to the concentration of these water-soluble vitamins in solution. In particular, Chien shows that it is necessary to have at least 9 mol of niacinamide in solution in order to solubilize 1 mol of metronidazole. In particular, Chien has shown that a combination of niacinamide with metronidazole in a molar ratio of 9 to 1 makes it possible to increase the solubility of metronidazole in an aqueous phase. Thus, in order to obtain a formulation containing 1% (m/m) of metronidazole solubilized in the aqueous phase, it is necessary to introduce a high niacinamide content on the order of 6.4% (m/m).
Y. Chang, G. Dow et al. describe in U.S. Pat. No. 6,468,989, on the basis of the studies by Chien et al., the use of cyclodextrins in combination with niacinamide in order to formulate gels containing 1% of metronidazole (m/m) with a niacinamide content below that of the prior art, i.e., only 1.25% (m/m). They have demonstrated a synergistic effect of the niacinamide/cyclodextrins combination on metronidazole solubility.